Obsessive-compulsive disorder (OCD) is the 4th most common mental disorder in the U.S. and is frequently disabling. From 20 percent to 40 percent of OCD patients do not respond satisfactorily to oral medications and an 8- to 10-week trial is needed to determine whether a given drug is effective for the patient. This study's broad, long-term objective is to investigate the efficacy, safety and rapidity of effect of a new treatment for these patients. We propose a 2-site, randomized, double-blind controlled trial in 76 patients with treatment-unresponsive DSM-IV OCD comparing pulse loaded intravenous clomipramine (CMI), (day 1, 150 mg; day 2, 200 mg; days 3-5, zero) to pulse loaded oral CMI (in identical doses) followed by 12 weeks of oral CMI treatment. Our primary Hypotheses are: 1. double-blind intravenous pulse loaded CMI will produce by day 6 a clinically meaningful improvement in OCD patients unresponsive to greater than or equal to 2 prior anti-OCD drug trials; 2. this improvement will significantly exceed that produced by oral pulse loaded CMI; and, 3. intravenous pulse loading patients will have experienced greater improvement by the end of a 12-week open-label oral CMI maintenance trial than oral pulse loading patients. Results of our double-blind Preliminary Study are consistent with these hypotheses. Power calculations based on a conservative effect size of 0.7 indicate that 76 patients would provide 80 percent power to test the Primary Hypotheses at p less than or equal to 0.05. We will also explore whether: 1. day 6 and week 12 outcomes are related to plasma levels Of CMI and its metabolites; and, 2. outcome can be predicted from baseline clinical information. (Throughout this revised grant application, revisions are indicated by bold type face, except that the new Introduction is in ordinary typeface).